Acute Allograft Failure Research Articles

Liver Retransplantation Using Living Donor Grafts: A Feasible Approach for Chronic Allograft Failure.

The indication of living donor liver retransplantation (re-LDLT) for retransplant candidates with chronic allograft failure (CAF) is increasing because of the high mortality rate of patients on the waiting list. However, evidence supporting re-LDLT for CAF remains scarce because of technical difficulties. We aimed to examine the feasibility based on our significant case experience. A total of 95 retransplant cases (adult: 53, pediatric: 42) between 2000 and 2020 were retrospectively reviewed. Graft survival after re-LDLT and deceased donor liver retransplantation (re-DDLT) was compared among recipients with CAF and acute allograft failure (AAF). Re-LDLTs for CAF were performed in 58 (61.1%) cases, re-DDLTs for CAF in 16 (16.8%) cases, re-LDLTs for AAF in 13 (13.7%) cases, and re-DDLTs for AAF in 8 (8.4%) cases. Re-DDLTs have become increasingly prevalent over time. Retransplantation for AAF results in lower graft survival than that for CAF in both adult and pediatric cases. All adult recipients who underwent re-LDLT for AAF died within 1 y after retransplantation. The 5-y graft survival between re-LDLT and re-DDLT for CAF was not significantly different (73.8% versus 75.0%, P = 0.84). Operation time and blood loss were not significantly different. The survival rate of re-LDLT for recipients with CAF is permissible. Re-LDLT may be another treatment option for recipients with CAF.

Characteristics of AMR Predicts Prognosis and Phenotype of CLAD

<h3>Purpose</h3> Antibody mediated rejection (AMR) has been linked to development of chronic lung allograft dysfunction (CLAD) either bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). It has never been assessed if AMR characteristics could predict evolution towards a phenotype of CLAD and post-treatment outcomes. <h3>Methods</h3> Data from patients treated for AMR in our center with antibody depleting therapy (ADT) (plasma exchange, high dose corticosteroids, rituximab and intravenous immunoglobulin) were reviewed. We subsequently distinguished patients presenting with late acute graft failure (LAGF) or not. LAGF was defined as acute allograft failure associated with radiological or histopathological signs compatible with acute fibrinous and organizing pneumonia (AFOP), diffuse alveolar damage (DAD) or organizing pneumonia (OP). Evolution towards CLAD and survival was investigated using Fisher's exact test and Kaplan-Meier survival curve with log-rank test. Predictive factors of death after treatment were analyzed using multiple stepwise logistic regression. <h3>Results</h3> Forty eight patients were treated with ADT for AMR. At baseline, 67% presented with CLAD (38% BOS, 44% RAS, 18% mixed). 71% presented with a clinical picture of LAGF while 29% did not. After ADT, for patients who survived long enough for reevaluation (n=42), there was a majority of patients who evolved towards a CLAD phenotype BOS in the group without LAGF (BOS n=9, RAS n=4, no CLAD n=1) and towards CLAD phenotype RAS in the LAGF group (BOS n=6, RAS n=21, no CLAD n=1) (P = 0.0148). Kaplan-Meier survival curves displayed lower survival for patients with AMR and LAGF versus patients with AMR without LAGF (P=0.0335) (figure 1). Multivariate analysis showed that LAGF (P=0.0388) and acute respiratory failure (P=0.0040) were independent predictive factors for death. <h3>Conclusion</h3> AMR may present in two distinct phenotypes: one with LAGF which evolves towards RAS with poor prognosis and a second without LAGF which evolves towards BOS with better outcomes after ADT.

Acute kidney rejection after anti-SARS-CoV-2 virus-vectored vaccine\u2014case report

COVID-19 infection remains a threat to the health systems of many countries. Potential success in the fight against the COVID-19 pandemic is the vaccination of high-risk groups, including patients with end-stage kidney disease (ESKD) and after solid organ transplantation (SOT). Immunosuppression in kidney transplant recipients can also reduce the immunogenicity of SARS-CoV-2 vaccines (varied by vaccine platform), available data suggest that they are efficacious in approximately 50–70%, compared to non-transplant situations. In this paper, we present a newly developed acute humoral and cellular rejection with acute allograft failure and need of hemodialysis 14 days after administration of the adenovirus vectored SARS-CoV-2 vaccine (AstraZeneca; CHADOx1, AZD1222). This occurred in a patient who previously had an asymptomatic COVID-19 infection. Case reports of acute allograft rejection after vaccination against SARS-CoV-2 can help stratify risk groups of patients who develop hyperimmune reactions. However, it is also possible that those with a previous mild primary COVID-19 infection may also develop acute allograft rejections upon COVID-19 re-infection.

Quiz: Acute Allograft Failure Nearly a Decade Posttransplantation

Quiz: Acute Allograft Failure Nearly a Decade Posttransplantation

Urinary Calprotectin Differentiates Between Prerenal and Intrinsic Acute Renal Allograft Failure

Urinary calprotectin has recently been identified as a promising biomarker for the differentiation between prerenal and intrinsic acute kidney injury (AKI) in the nontransplant population. The present study investigates whether calprotectin is able to differentiate between these 2 entities in transplant recipients as well. Urinary calprotectin was assessed by enzyme-linked immunosorbent assay in 328 subjects including 125 cases of intrinsic acute allograft failure, 27 prerenal graft failures, 118 patients with stable graft function, and 58 healthy controls. Acute graft failure was defined as AKI stages 1 to 3 (Acute Kidney Injury Network criteria), exclusion criteria were obstructive uropathy, urothelial carcinoma, and metastatic cancer. The clinical differentiation of prerenal and intrinsic graft failure was performed either by biopsy or by a clinical algorithm including response to fluid repletion, history, physical examination, and urine dipstick examination. Reasons for intrinsic graft failure comprised rejection, acute tubular necrosis, urinary tract infection/pyelonephritis, viral nephritis, and interstitial nephritis. Calprotectin concentrations of patients with stable graft function (50.4 ng/mL) were comparable to healthy controls (54.8 ng/mL, P = 0.70) and prerenal graft failure (53.8 ng/mL, P = 0.62). Median urinary calprotectin was 36 times higher in intrinsic AKI (1955 ng/mL) than in prerenal AKI (P < 0.001). Receiver-operating characteristic curve analysis revealed a high accuracy of calprotectin (area under the curve, 0.94) in the differentiation of intrinsic versus prerenal AKI. A cutoff level of 134.5 ng/mL provided a sensitivity of 90.4% and a specificity of 74.1%. Immunohistochemical stainings for calprotectin in renal allograft biopsy specimens confirmed the serological results. Urinary calprotectin is a promising biomarker for the differentiation of prerenal and intrinsic acute renal allograft failure.

Intragraft vascular occlusive sickle crisis with early renal allograft loss in occult sickle cell trait

Early renal allograft failure due to sickle cell trait is rare. We present clinical and pathologic findings in 2 cases of early renal allograft failure associated with renal vein thrombosis and extensive erythrocyte sickling. Hemoglobin AS was identified in retrospect. In case 1, a 41-year-old female recipient of a deceased donor renal transplant developed abdominal pain and acute allograft failure on day 16, necessitating immediate nephrectomy. In case 2, the transplanted kidney in a 58-year-old female recipient was noted to be mottled blue within minutes of reperfusion. At 24 hours, the patient was oliguric; and the graft was removed. Transplant nephrectomies had diffuse enlargement with diffuse, nonhemorrhagic, cortical, and medullary necrosis. Extensive sickle vascular occlusion was evident in renal vein branches; interlobar, interlobular, and arcuate veins; vasa recta; and peritubular capillaries. The renal arteries had sickle vascular occlusion in case 1. Glomeruli had only focal sickle vascular occlusion. The erythrocytes in sickle vascular occlusion had abundant cytoplasmic filaments by electron microscopy. Acute rejection was not identified in either case. Protein C and S levels, factor V Leiden, and lupus anticoagulant assays were within normal limits. Hemoglobin analysis revealed hemoglobin S of 21.8% and 25.6%, respectively. Renal allograft necrosis with intragraft sickle crisis, characterized by extensive vascular occlusive erythrocyte sickling and prominent renal vein thrombosis, was observed in 2 patients with sickle cell trait. Occult sickle cell trait may be a risk factor for early renal allograft loss.

Peginterferon α-2b and Acute Allograft Failure in a Heart Transplant Recipient

Reports of heart transplant recipients with hepatitis C viral infection treated with peginterferon alpha-2b and ribavirin are very rare. We report a fatal case of acute allograft failure and hepatitis C viral infection in a 50-year-old orthotopic heart transplant recipient. At autopsy, the patient was found to have patent coronary arteries, diffuse severe fatty degeneration of heart myocytes, and no evidence of cellular or humoral rejection, confirming this as a fatal case of cardiotoxicity from peginterferon alpha-2b.

Surgical treatment of heart failure: heart transplantation and ventricular restoration surgery

Heart transplantation (HT) is the only established surgical approach to the treatment of refractory heart failure. Survival after HT in Spain is 80% at 1 year, 70% at 5 years, and 60% at 10 years. The causes of death after HT depend on the time elapsed since transplant. In the first month, deaths are due mainly to acute allograft failure, between months 1 and 12 to infection and rejection, and thereafter to neoplasia, sudden cardiac arrest, or allograft vasculopathy. The main limitation on the application of HT to appropriately selected HF patients is the shortage of donors. Ventricular restoration surgery (VRS) comprises a set of surgical procedures for prevention of post-infarction ventricular remodelling. These techniques aim to reduce the volume and restoring the elliptical shape of the left ventricle by exclusion of the infarcted non-contracting segment. No randomized studies assessing the efficacy of VRS have yet been completed, and the results of the international multicentre trial STICH, in which patients with ischaemic cardiomyopathy are randomized to medical therapy, coronary bypass alone, or coronary bypass with VRS, are eagerly awaited. However, data from a large registry of patients with VRS show good results, with an overall 30-day mortality of 5.3% and a 5-year survival rate of 68%.

Cardiac Surgery in Renal Transplant Recipients: Experience from Washington Hospital Center

The number of renal transplant survivors requiring surgical treatment for cardiovascular diseases is increasing. A retrospective study was conducted to determine the outcomes of renal transplant recipients undergoing cardiac surgery. Fifty-seven renal transplant recipients whose cardiac surgery was performed between 1987 and 2004, and whose allograft was functioning at the time of cardiac surgery, were identified. We analyzed postoperative mortality and morbidity as well as late mortality. Among 57 patients, 70.2% had hypertension, 54.4% diabetes, and 28.1% poor left ventricular function (ejection fraction < 0.35). Preoperative renal insufficiency (serum creatinine level > or = 3 mg/dL) was noted in 12.3% of the patients. Coronary artery disease was the dominant indication for the surgery. The median interval from renal transplant to cardiac surgery was 60 months. In-hospital mortality was 5.3%. All deaths were cardiac-related. Infectious complications occurred in 17.5% of the patients. Acute allograft failure requiring hemodialysis occurred in 28.6% of the patients with preoperative renal insufficiency, more frequent than those without preoperative renal insufficiency. Multivariable analysis identified preoperative renal insufficiency, mitral valve disease, and left ventricular dysfunction as independent predictors of in-hospital major adverse events (including death, infection, and renal failure). The 3-year survival was 71% after a median follow-up of 34 months. Infection control and renal protection should be stressed to ensure the safety of cardiac surgery in this patient group, while preoperative renal insufficiency, mitral valve disease, and left ventricular dysfunction are associated with early adverse outcomes. In the renal transplant recipients undergoing an isolated CABG, avoidance of cardiopulmonary bypass and use of arterial grafts might lead to better outcomes.

A 37-year-old woman with systemic lupus erythematosus and acute allograft failure

THE RENAL BIOPSY is considered the gold standard method for the diagnosis of the processes that cause graft dysfunction. Complete morphological studies must be systematically applied to these samples to specifically assess the etiology of those processes. The likelihood of a particular etiology largely depends on the interval since transplantation. In the early posttransplantation period, most cases of renal dysfunction are etiology by acute tubular necrosis, reperfusion injury, acute rejection, drug toxicity, obstruction, surgical complications, or infection. Later in the time course, other causes of graft dysfunction include chronic transplant nephropathy, cyclosporine toxicity, and recurrent or de novo glomerular diseases. However, recurrent disease also should be considered in some cases in the immediate posttransplantation period. We present a renal transplant recipient with systemic lupus erythematosus (SLE) and early allograft dysfunction and rapid graft failure. The serial biopsies and complete morphological studies permitted a specific diagnosis in this case.

Clinico-pathologic, Immunohistochemical, and TUNEL Study in Early Cardiac Allograft Failure

Early cardiac allograft failure (ECAF) was defined as acute allograft failure in the early transplant period. The aim of this study is to elucidate the clinicopathological and immunohistochemical characteristics and the role of apoptosis in ECAF in nine patients. We reviewed preoperative clinical data and morphological data at the time of autopsy or retransplantation. We also performed TUNEL assay and immunohistochemistry to study fibronectin and tubulin β-II. The average recipient and donor age was 48 ± 10.3 and 28 ± 7.11 respectively. Seven patients died at a mean time of 26 hours. The remaining two patients underwent retransplantation and are alive. The mean cold ischemic time was 124.1 ± 44.5 minutes. No patient had a panel reactive antibody >15% and lymphocytic crossmatch was positive in one case. All cases had grade 2-3 of coagulative necrosis, which correlated positively with fibonectin accumulation in myocyte cytoplasm, and cytoplasmic tubulin loss (p < 0.05). TUNEL technique showed in all cases some degree of DNA strand breaks in cardiomyocytes. Endothelium DNA strand breaks were seen in seven cases. Patients transplanted because of idiopathic dilated cardiomyopathy had a significantly higher degree of DNA strand breaks in cardiomyocytes and endothelial cells (p = 0.03 and p = 0.02) than those transplanted because of ischemic cardiomyopathy. These results indicate that ECAF may be caused by ischemic-reperfusion damage to the donor heart assessed by myocyte coagulative necrosis, fibronectin accumulation in myocytes, tubulin loss, and DNA strand breaks of cardiomyocytes and endothelium. The use of a combination of these techniques might be appropriate in the diagnosis of ECAF in endomyocardial biopsies when it is suspected clinically.

Contribution of IFN-?? to acute allograft failure in murine cardiac transplants: Role in vascular thrombosis

Contribution of IFN-?? to acute allograft failure in murine cardiac transplants: Role in vascular thrombosis

Contribution of IFN-γ to acute allograft failure in murine cardiac transplants: Role in vascular thrombosis

390 We investigated the role of IFN-γ in acute cardiac allograft failure using IFN-γ deficient (GKO) mice. Without immunosuppression, BALB/c[H-2d] into wild type C57BL/6 [B6, H-2b] total allogeneic mismatched cardiac grafts ceased beating at 7.2 ± 0.2 days (n=9); BALB/c hearts transplanted into B6GKO ceased beating at 6.6 ± 0.1 days(n=6). Although grafts in both wild type and GKO recipients showed comparably severe mononuclear cell infiltration (rejection), allografts in GKO recipients also showed profound acute coagulation necrosis with vascular thrombosis demonstrable by fibrin staining. By immunohistochemical staining, plasminogen activator inhibitor-1 (PAI-1) was strikingly increased in allografts transplanted into B6GKO hosts relative to B6 wild types; no difference was seen in tissue plasminogen activator staining for allografts in wild type vs GKO hosts. Without immunosuppression, MHC I-mismatched allografts, characterized by a predominant CD8 T cell response (bml into B6), functioned for at least 12 weeks (n=10) and showed only moderate acute rejection. In contrast, bml into B6GKO allografts ceased beating at 7.7 ± 0.7 days(n=7), and showed rejection with coagulative necrosis and vascular thrombosis. Without immunosuppresiosion, MHC II-mismatched allografts, characterized by a predominant CD4 T cell response (bml2 into B6), ceased beating at 31.5± 6.2 days (n=6), and showed severe rejection. In contrast, bml 2 into B6GKO allografts functioned for at least 12 weeks and showed only moderate rejection without coagulative necrosis or vascular thrombosis. To specifically evaluate the role of T cell subpopulations, CD4 and/or CD8 T cells were selectively depleted in recipients by appropriate mAb administration pre-transplant, as shown below. Graft survival times were: BALB/c into B6(anti-CD4): 38.3 ± 6.7 days (n=3), BALB/c into B6GKO (anti-CD4): 10.7± 5.0 days (n=3), BALB/c into B6 (anti-CD8): 12.0 ± 2.3 days(n=5), BALB/c into B6GKO (anti-CD8): 14.3 ± 1.5 days (n=3), BALB/c into B6 (anti-CD4 and CD8): 31.7 ± 3.2 days (n=9), BALB/c into B6GKO(anti-CD4 and CD8): 38.2 ± 7.3 days (n=5). All grafts in the above demonstrated comparably severe rejection; notably, coagulative necrosis and thrombosis were not seen. The results suggest that acute cardiac allograft failure, particularly in GKO, may include a component of vascular thrombosis due to increased PAI-1 activity. Increased thrombosis is particularly evident in the setting of MHC I mismatches, but cannot be wholly attributed to an effect of CD8T cells.

Do calcium channel blockers and HMG-CoA reductase inhibitors attenuate allograft arteriopathy?

Recent epidemiologic studies of the risk factors for early and late phases of transplant coronary artery disease (TxCAD) have identified metabolic abnormalities such as hyperlipidemia and insulin resistance as important risk factors, independent of rejection. In randomized trials, calcium channel blockers and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were shown to decrease coronary artery intimal thickening and stenosis. Furthermore, HMG-CoA reductase inhibitors significantly decreased allograft loss during the first year after transplantation, resulting in a survival benefit, independent of TxCAD and cholesterol lowering. Prevention of acute allograft failure is consistent with known immunomodulatory actions of HMG-CoA reductase inhibitors, and the effects of calcium blockers in preventing TxCAD might have an immunologic basis by virtue of alterations of cyclosporine pharmacodynamics. Hence these two strategies for targeting antigen-independent mechanisms should lead to a significant reduction in the incidence of TxCAD, a goal that has until this time defied all the advances in immunosuppression during the past three decades of heart transplantation.

Primary Graft Failure after Heart Transplantation. Successful Recovery with Pneumatic Biventricular Assistance

A 41-year-old male underwent orthotopic heart transplantation complicated by intraoperative acute allograft failure. The patient required immediate placement of a pneumatic biventricular assist device which was kept for 49 days until graft recovery resulted in successful explantation of the device. The patient was discharged from hospital on postoperative day 112. Management of primary cardiac allograft failure with mechanical ventricular assistance is discussed.

Predictors of operative mortality and morbidity after infant heart transplantation

We retrospectively analyzed the impact of recipient, donor, and operative factors on the operative mortality and morbidity of 36 consecutive infant heart transplantations. Operative survival was excellent at 94%. Among 34 survivors, operative morbidity in 12 patients included acute severe allograft failure with or without prolonged ventilatory support. The cohort was characterized by age less than 4 months (32 of 36), a diagnosis of hypoplastic left heart syndrome (29 of 36), and the use of circulatory arrest (27 of 36); these variables were colinear and could not be used to predict operative mortality or morbidity. None of the remaining recipient, donor, or operative characteristics predicted survival or acute severe allograft failure. A donor-to-recipient weight ratio greater than 2 and a circulatory arrest time greater than 39 minutes predicted the need for prolonged ventilatory support. Despite the need for aggressive or prolonged support after 12 of 36 transplantations, operative survival was high at 94% (34 of 36 procedures, 32 of 34 patients). The use of less restrictive donor criteria combined with aggressive management of acute allograft failure can result in excellent operative survival after infant heart transplantation.